Ace enzyme
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Understanding the Role of ACE and ACE2 Enzymes
Introduction to ACE and ACE2 Enzymes
Angiotensin-converting enzyme (ACE) and its homologue, ACE2, are critical components of the renin-angiotensin system (RAS), which regulates blood pressure and fluid balance. ACE is a dipeptidyl carboxypeptidase that converts angiotensin I into the potent vasoconstrictor angiotensin II, playing a pivotal role in cardiovascular function . ACE2, on the other hand, has a more restricted expression pattern and distinct substrate specificity, converting angiotensin I to angiotensin 1-9 and degrading angiotensin II to the vasodilator angiotensin 1-7 .
Structural and Functional Differences Between ACE and ACE2
Structural Insights
ACE and ACE2 share significant structural similarities, including a zinc-binding metalloprotease domain. However, ACE2 has unique structural features that confer different substrate specificities. The active site of ACE2, modeled based on the crystal structure of testicular ACE, reveals differences in the ligand-binding pockets, particularly at the S2' subsite, which explains why classical ACE inhibitors like lisinopril do not inhibit ACE2 . Additionally, ACE2 exhibits a large hinge-bending motion important for inhibitor binding and catalysis, which is not observed in ACE.
Functional Specificities
ACE is a relatively nonspecific peptidase capable of cleaving a wide range of substrates, affecting various physiological processes such as blood pressure control, renal function, and immune response. In contrast, ACE2 has a more specialized role, primarily in the heart, kidney, and testis, where it modulates the balance between vasoconstrictors and vasodilators, thus playing a significant role in cardiovascular and renal function .
Biological Roles of ACE2
Cardiovascular and Renal Regulation
ACE2 acts as a counter-regulatory enzyme to ACE, balancing the effects of angiotensin II by converting it to the vasodilator angiotensin 1-7. This function is crucial in maintaining cardiovascular and renal health, as it helps modulate blood pressure and fluid balance . The organ-specific expression of ACE2, particularly in the heart and kidney, underscores its importance in these systems .
Testicular Function
In the testis, ACE2 is selectively expressed by Leydig and Sertoli cells, suggesting a role in testicular function and development. The enzyme's activity in these cells is upregulated during puberty and after specific treatments, indicating its involvement in the maturation and function of adult-type Leydig cells.
Interaction with Integrins
Recent studies have shown that both ACE and ACE2 can bind integrin subunits, acting as cell adhesion substrates. ACE2 enhances cell adhesion and modulates integrin signaling, which may influence cell survival and proliferation. This interaction suggests a role for ACE2 in cell-extracellular matrix interactions and pathological cardiac remodeling.
Role in SARS-CoV-2 Infection
ACE2 is also known as the functional receptor for the SARS coronavirus, which causes severe acute respiratory syndrome (SARS). The downregulation of ACE2 during infection contributes to severe lung failure, highlighting its protective role in lung physiology.
Conclusion
ACE and ACE2 are integral to the renin-angiotensin system, with ACE primarily involved in generating vasoconstrictors and ACE2 acting as a counter-regulatory enzyme producing vasodilators. The structural and functional differences between these enzymes allow them to play distinct yet complementary roles in cardiovascular, renal, and testicular functions. Additionally, ACE2's involvement in integrin signaling and as a receptor for SARS-CoV-2 underscores its multifaceted biological significance. Understanding these enzymes' roles and mechanisms can pave the way for novel therapeutic strategies in treating cardiovascular diseases and other related conditions.
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